Process for producing rhein and diacerhein

ABSTRACT

The following description sets forth a process for producing rhein, diacerhein and other diacyl derivatives thereof, which comprises the following steps: treatment of a diphenylketone ##STR1## in which R 1  is --OR&#39;, --NR&#39;R&#34;, --SR&#39;, where R&#39; and R&#34; are H, an alkyl or aromatic group; R 2  is H or a protective group, R 3  is --OH or C 1  -C 4  alkyl, with an acid or superacid to give a 1-aminoanthraquinone derivative, diazotisation, replacement of the --NH 2  group by --OH, optional removal of the protective group, and acylation.

FIELD OF THE INVENTION

The present invention relates to a process for producing diacerhein from synthetic raw materials.

PRIOR ART

Rhein and several analogues thereof, the 1,8-diacyl derivative (diacerhein) being particularly important, are known for use in the treatment of degenerative diseases of the joints, such as osteoarthritis and connective tissue matrix diseases, for example osteoporosis and rheumatoid arthritis (GB 1,578,452).

Diacerhein is commercially available in the form of pharmaceutical preparations, such as Artrodar ^(R).

The only process for diacerhein synthesis utilized at present on a commercial scale is based on the use of aloin as starting material (European patent application No. 0 636 602 A1, by the Applicant). DE 80,407 and U.S. Pat. No. 3,089,879-A describe ring closure of 2,4'-benzophenone dicarboxylic acid to 2-carboxy-antraquinone by treatment with sulphuric acid.

Japanese application JP 49/45050 reports acid catalyzed cyclization of 2-(2'-aminobenzoyl)-benzoic acid to 1-aminoantraquinone.

In principle, two isomeric substituted 1-aminoantraquinones can be formed by cyclization of substituted 2-(2'aminobenzoyl)-benzoic acid. So these documents do in no way suggest that ring closure to 1-aminoantraquinone of diarylketones of formula (II) according to step a) of the present process as below illustrated allows the isomeric derivative of formula (III) to be obtained in high yield and in pure form.

TECHNICAL PROBLEM

Aloin is obtained from natural sources via laborious extraction and purification procedures consuming large amounts of vegetable raw materials.

Furthermore, since the market price of the raw material of vegetable origin fluctuates periodically, it is hardly possible to develop large-scale commercial processes manufacturing products from said raw material at the estimated cost. This is a serious disadvantage in the pharmaceutical sector, the prices of pharmaceuticals being strictly governed by the regulations in force.

Therefore, the need for a commercial-scale process for the production of diacerhein of good purity and in satisfactory yields not requiring the use of aloin or other raw materials of extractive origin is deeply felt.

SUMMARY

The Applicant has surprisingly found a process for producing rhein and related diacyl derivatives, e.g. diacerhein, of formula (I) ##STR2## in which R_(A) is H, acyl, alkyl or aromatic group, comprising the steps of:

a) treating a diphenylketone of formula (II) ##STR3## in which R₁ is --OH, --OR', --NH₂, --NHR', --NR'R", --SH or --SR', where R' and R", which may be the same or different one from another, each represents alkyl or aromatic groups,

R₂ is H or a protective group of the --OH function,

R₅ is H or C₁ -C₄ alkyl,

with a strong concentrated acid (e.g. superacid) to give the 1-aminoanthraquinone derivative of formula (III) ##STR4## in which R₁ and R₂ are as defined above; b) converting the --NH₂ group to --OH, via the following steps:

b') treating the derivative of formula (III) obtained in step a) with a diazotising agent, and

b") warm treating the product resulting from step b') with a strong acid in an aqueous medium to give the compound of formula (IV) ##STR5## in which R₂ is as defined above; c) when R₂ is a protective group, removing R₂ in any process step, on the compound of formula (II), (III) or (IV), in which R₂ is a protective group as defined above, to give the rhein of formula (V) ##STR6## d) when R_(A) is acyl, treating the rhein of formula (V) with an acylating agent.

The rhein of formula (V) may be optionally converted to the corresponding ethers of formula (I), in which R_(A) is an alkyl or aromatic group, by conventional methods, e.g. by treatment with bases (e.g. NaH) and with the corresponding etherifying agents, e.g. alkylating agents, such as R_(A) Hal halides., where R_(A) is the alkyl or aromatic group and Hal is a halogen.

This invention also provides a diphenylketone of formula (II), the 1-aminoanthraquinone derivative of formula (III), a compound of formula (IV) and the diazo derivative of formula (VI) described hereinafter.

It is a further object of the present invention to provide a process for producing a diphenylketone of formula (II) as defined in the aforementioned step a), comprising the steps of:

1) treating the phthalic acid derivative of formula (VII) ##STR7## in which R₂ is a protective group of the --OH function, with a hydroxylated compound, R₃ OH, in which R₃ is an alkyl group, in the presence of a Cu(I) salt, in an acid medium, to give a monoester of formula (VIII) ##STR8## in which R₂ and R₃ are as defined above for this step; 2) treating the derivative of formula (VIII) obtained in step 1) with a halogenating agent of the carboxylic function to give an acyl halide of formula (IX) ##STR9## in which R₂ and R₃ are as defined under 1), and Hal is a halogen;

3) treating the resulting derivative of formula (IX) with the derivative of formula (X) ##STR10## in which R₁ is --OR', --NHR', --NR'R" or --SR', and where R', R", R₄, which may be the same or different one from another, each represents alkyl (identical to or different from R₃) or aromatic groups,

in the presence of a Friedel-Crafts catalyst, to give the protected diphenylketone of formula (XI) ##STR11## in which R₁, R₃ and R₄ are as defined under 2) and R₂ is as defined under 1);

4) treating the protected diphenylketone of formula (XI) with a strong base, in an aqueous medium, and acidifying to give the diphenylketone of formula (II)A ##STR12## in which R₂ is as defined under 1).

The derivative of formula (II)A may be converted to the corresponding derivatives of formula (II), in which R₁ is --OR', --NR'R", --NHR', --SH or --SR' as defined above, e.g. by treatment with the corresponding alcohol, amine or thiol (e.g. with R'OH, R'R"NH or R'SH), by conventional methods.

The invention also provides dimethylketones of formulas (XI) and (II)A.

The process of the invention produces pure diacerhein in high yields. While the products obtained by the processes of the prior art always contain aloe-emodin at least in trace amounts as a result of the use of raw materials of natural origin (e.g., extracts of senna leaves or barbaloin)--said impurity exerting mutagenic action even in amounts as low as 70 ppm--the intermediates and final products obtained by the claimed process are totally free from aloe-emodin, i.e. no ppm or even ppm fractions thereof are present, since the present process exclusively utilizes aloe-emodin free synthetic starting materials, which, in no process phase, bring about formation of said impurity. Also, this invention further extends to i) compounds selected among the derivatives of formula (I), in which R_(A) is H, acyl, alkyl or aromatic group, in particular diacerhein and pharmaceutically and cosmetically acceptable salts or derivatives thereof (e.g. esters, amides or thioesters), ii) pharmaceutical compositions for human or veterinary use containing a therapeutically effective amount of at least one of said compounds, combined with at least one pharmaceutically acceptable excipient and/or diluent, and optionally with one or more auxiliary substances, and iii) cosmetic preparations comprising at least one of said compounds, characterized in that said compounds, compositions and cosmetic preparations are completely free from aloe-emodin and/or from the derivatives of formula (I) analogous thereto, in which the --CH₂ OH group replaces the --COOH group.

The pharmaceutical compositions and cosmetic preparations of the present invention may be prepared by conventional methods.

The present pharmaceutical compositions free form aloe-emodin find the same therapeutic application (especially in human therapy), known for compounds of formula (I), in particular in the treatment of inflammatory states such as degenerative joints diseases, and are administered at unit dosages and daily dosages known for present derivatives of formula (I).

DETAILED DESCRIPTION OF THE INVENTION

As used herein, the alkyl groups are preferably C₁ -C₂₀ alkyl groups and more preferably short-chain alkyl groups (e.g. C₁ -C₄). Furthermore, saturated, straight or branched alkyl groups are preferred; however, they may optionally contain one or more unsaturations, e.g. one or more double bonds and/or be substituted, e.g., with alkoxy or phenoxy groups.

The aromatic substituents optionally present in the R₁ group or as R₃, R₄ or R_(B) groups are preferably carbocyclic (monocyclic or polycyclic) C₆ -C₂₀ aromatic groups, e.g. phenyl.

When R_(A) is acyl, it may in particular be R_(B) CO-, where R_(B) is an alkyl or aromatic group, typically C₁ -C₄ alkyl.

The R', R", R₃ and R₄ groups are preferably short-chain alkyl groups, typically C₁ -C₄ alkyl groups, i.e. containing 1 to 4 carbon atoms, more preferably --CH₃ groups.

In the derivatives of formula (II), R₅ is preferably H and, when R₅ is C₁ -C₄ alkyl, is preferably --CH₃.

R₂ is typically a protective group removable in an acid medium and stable to the bases, preferably an alkyl group, typically saturated and having a straight or branched short chain (e.g. C₁ -C₄), preferably --CH₃.

The R₁, R₂, R₃ and R₄ groups, present in the various chemical intermediates mentioned herein, may be varied, from one step to the other of the claimed processes, by known methods, depending on the requirements and according to the meanings reported herein or to equivalent meanings.

For the purposes of the present invention, preferred groups of compounds are of formulas (II) and (III) above, in which R₁ is --OH, R₂ is a saturated straight or branched alkyl group containing 1 to 4 carbon atoms (C₁ -C₄), and for compounds of formula (II), R₅ is H; especially preferred are compounds of formulas (II) and (III) above in which R₁ is --OH, R₂ is --CH₃, and for compounds of formula (II), R₅ is H.

The compounds of formula (III) in which R₁ is --OH, may be converted to the corresponding compounds of formula (III), in which R₁ is OR', by treatment with an alcohol R'OH, in the presence of an acid catalyst, according to conventional methods.

Out of the compounds of formula (IV), the compounds in which R₂ is a saturated, straight or branched C₁ -C₄ alkyl group, and in particular CH₃, are preferred.

When R₁ is --OR', --NR'R" or SR', R₁ conversion to --OH typically takes place in an aqueous acid medium, in steps b') or b"), and especially in step b"). yielding the corresponding phenol derivative of formula (IV) wherein the carboxyl function is free; alternatively, it may be carried out by a further hydrolysis step, i.e. acid or basic.

Preferably, the reaction mixture coming from diazotisation (step b') is directly subjected to step b") without prior isolation of the intermediate diazo derivative.

Step c), i.e. removal of protective group R₂, is preferably a step of acid hydrolysis, in an aqueous medium, of the compound of formula (II) or (III) or (IV), more preferably of formula (IV), in which R₂ is a protective group removable in an acid medium, typically C₁ -C₄ alkyl.

Step c) is preferably carried out as the last step of the synthesis after performing, in sequence, steps a), b') and b"), on the compound of formula (IV) coming from step b"), in which R₁ is as defined above and R₂ is a protective group as defined above.

According to a preferred embodiment of the present invention, step a) utilizes the diphenylketone of formula (II), in which R₅ is H, R₁ is --OH, and R₂ is a C₁ -C₄ alkyl group, preferably saturated, straight or branched, more preferably CH₃, to give the corresponding 1-aminoanthraquinone derivative of formula (III), in which R₁ is --OH and R₂ is a saturated, straight or branched C₁ -C₄ alkyl group, preferably CH₃ ;

the reaction mixture from step b') is directly subjected to step b"), without prior isolation of the intermediate diazo derivative, to give the corresponding phenol derivative of formula (IV), in which R₂ is a saturated, straight or branched C₁ -C₄ alkyl;

in step c), the derivative of formula (IV) as obtained above is subjected to acid hydrolysis to give the rhein of formula (V).

According to a still more preferred embodiment of the present invention, the derivative of formula (I) is diacerhein, in which R_(A) is --OCOCH₃. Therefore, the process according to the present invention comprises acetylation (step d).

The strong acids suitable for the conversion of diphenylketone of formula (II) to the 1-aminoantraquinone derivative of formula (III) according to the present invention are for instance either mineral (inorganic) or organic acids, such as sulphuric acid and CF₃ SO₃ H. For the present purposes, concentrated acids typically have a concentration of about at least 90%, e.g. of about 95%-98% weight by weight (w/w) of acid, e.g. in water.

In present step a) , superacids such as fuming sulphuric acid (H₂ SO₄.SO₃, also known as oleum, with variable amount of SO₃ or CF₃ SO₃ can be used, or concentrated sulphuric acid (e.g. about 95%-98% w/w). According to particular embodiments of the present invention, concentrated sulphuric acid or CF₃ SO₃ H can be used, more preferably CF₃ SO₃ H.

Step a) is preferably carried out at a temperature approximately ranging from 0° C. to 250° C., preferably from 100° C. to 200° C., and more preferably from about 140° C. to 160° C.

For example, the diphenylketone of formula (II) and the selected strong concentrated acid are mixed under stirring at a temperature ranging from 0° C. to room temperature (about 20° C. to 30° C.); then the temperature is gradually raised preferably to a value ranging from about 100° to about 200° C., typically at least about 140° C. to 160° C.

The diphenylketone of formula (II)/acid ratio typically ranges from 0.5:1 to 4.75:1, e.g. about 1:3, expressed as mmols of product (II) per ml of strong acid.

The product of formula (III) is isolated by conventional methods: in particular it precipitates from the reaction medium, generally in the form of crystals, after neutralization with a strong base, e.g. NaOH, preferably added at a low temperature. e.g. 4° C. to 8° C., and is separated from the liquid phase by conventional methods, e.g. filtration.

Diazotisation (step b') is preferably carried out by cold treating the product of formula (II) with nitrous acid, in an aqueous medium; the reaction temperature preferably ranges from 0° C. to 8° C., more preferably from about 0° C. to 5° C.

Nitrous acid is preferably generated in the reaction medium by the action of a strong acid (e.g. an inorganic acid, such as H₂ SO₄, or an organic acid, such as CF₃ SO₃ H, preferably H₂ SO₄) on a nitrite, typically an alkali metal nitrite, such as NaNO₂.

For example, step b') is carried out with NANO₂, in a concentrated H₂ SO₄ /water mixture in a ratio ranging from 1:1 to 1:3 (volume/volume =v/v).

The diazotising agent is typically used in molar excess of the compound of formula (III), in a quantity ranging, e.g., from about 1.1 to 2.0 mol, preferably of about 1.5 mol per mol of (III).

The diazotised intermediate of formula (VI) ##STR13## in which R₁ and R₂ are defined as for the dimethylketone of formula (II), can be isolated from the medium of diazotisation (step b'), e.g. by filtration.

X is the anion of the strong acid, in whose presence diazotisation is carried out;

n is the number (integer) corresponding to the number of negative charges of said anion;

when R₁ is H, m is (n-1), or, when R₁ is different from H, m=n. The diazo derivative of formula (VI) is preferably the one in which R₁ is --OH, and R₂ is C₁ -C₄ alkyl, in particular CH₃ ; furthermore, X is preferably SO₄ ²⁻ (n=2), and m is 1.

In step b") the strong acid is, e.g., an inorganic acid, such as sulphuric acid, or an organic acid, such as CF₃ SO₃ H; sulphuric acid is typically used.

Step b") is generally carried out at a temperature ranging from 100° C. to 250° C., preferably of about 140° C. to 150° C. Under typical conditions, the reaction medium of steps b') and b") is a strong acid/water mixture in a ratio preferably ranging from 1:0.5 to 1:5, more preferably from 1:1 to 1:3 (v/v).

Furthermore, step b') is preferably carried out with ratios of the derivative of formula (III) to the reaction medium ranging from 1:0.5 to 1:5, typically 1:3, expressed as mmols of (III) per ml of reaction medium; step b") is preferably carried out with ratios of substrate [derivative of formula (III) or derivative of formula (VI)] to the reaction medium typically equal to about 1:3, expressed as mmols of the derivative of formula (III) or (VI) per ml of reaction medium (typically a strong acid/water mixture).

The resulting phenol derivative of formula (IV) is easily isolated from the acid reaction mixture by cooling to room temperature and collecting the precipitate, e.g. by filtration.

As mentioned above, step b") is preferably carried out on the reaction mixture from step b'), optionally diluted, without prior isolation of the diazotisation product. For example, diazotisation is carried out in an acid aqueous medium, e.g. by optionally diluting with additional strong acid/water mixture the reaction mixture from step b'), then heating to the temperature of step b").

Acid hydrolysis as per step c) is preferably carried out at a temperature ranging from about 90° C. to about 160° C., more preferably from about 100° C. to about 120° C.

Preferably, step c) is carried out with concentrated HBr (about 48% HBr aqueous solution) and glacial acetic acid as diluent; the temperature is preferably the reflux temperature of the reaction mixture.

The quantity of concentrated HBr ranges, e.g., from about 0.1 ml to 10 ml, typically from 0.5 ml to 3 ml of concentrated HBr per mmol of substrate of formula (II), (III) or (IV).

The quantity of glacial acetic acid ranges about from 5 to 20 ml, e.g. about 10 ml per mmol of substrate to be treated.

Under the conditions reported above, the reaction product from step c), in particular the rhein of formula (V), generally precipitates in the reaction medium at room temperature, wherefrom is separated by conventional methods, e.g. by filtration in vacuo; then it is preferably purified by crystallization, e.g. from an alcohol, such as methanol.

The synthesis reactions as per steps a), b'), b") and c) described above are completed within short times, generally ranging from about 15 min. to 2-14 3 hrs., and give highly pure products in high yields. Preferably, the derivative of formula (I) is the one in which R_(A) is --COCH₃ (diacerhein).

Preferably, the rhein of formula (V) is prepared through steps a), b'), b") and c) defined above and converted to the acyl derivative, preferably diacerhein, via step d).

Treatment with the acylating agent as per step d) is carried out at temperatures preferably ranging from about 50° C. to about 100° C., e.g. from about 70° C. to 90° C.

The acylating agent is, e.g., the anhydride or acyl halide of the R_(B) COOH acid, where R_(B) is as defined above.

The halide is typically used in the presence of a base as protons acceptor, and the anhydrides are used in the presence of an acid or basic catalyst; the acid catalyst may be, e.g., an organic acid, such as acetic acid, methanesulphonic acid, trifluoromethanesulphonic acid, or an inorganic acid, such as concentrated sulphuric acid, preferably H₂ SO₄ ; the basic catalyst may be, e.g., an organic base, typically an alkali metal acetate, such as sodium acetate, or an inorganic base, such as an alkali metal bicarbonate, e.g. NaHCO₃.

Preferably, the acylating agent is acetic anhydride, an acetyl halide, such as the chloride, typically used in the presence of a base as a protons acceptor, or hexachloroacetone.

Acetic anhydride in the presence of an acid or basic catalyst is preferably used.

The acylating agent (typically acetic anhydride) is generally in stoichiometric excess in respect of rhein, e.g. it amounts to from 2.0 to 5.0 mols, preferably 3.0 mols per mol of rhein.

Preferably, rhein is treated with acetic anhydride, in glacial acetic acid as reaction solvent, the solvent being in an amount ranging, e.g. from about 0.5 to about 5 ml, typically of about 1 ml per mmol of rhein, in the presence of a catalytic quantity of concentrated H₂ SO₄. Diacerhein is easily isolated from the reaction medium as it precipitates by cooling to room temperature and is separated by conventional methods, such as filtration.

The diphenylketone of formula (II) is a novel product synthesized by the Applicant from commercially available compounds. The derivative or-formula (VII) is obtained, e.g., by oxidation of the dimethylbenzene derivative of formula (XII) ##STR14## in which R₂ is a protective group of the --OH function, preferably a saturated, straight or branched C₁ -C₄ alkyl group, with an oxidizing agent, preferably a hypochlorite (such as NaCl0), and with an alkyl halide, preferably containing 1 to 6 carbon atoms (such as n-butylbromide) , in the presence of a transition metal salt (preferably a Ru(III) salt, such as RuCl₃). preferably operating in an aqueous medium, at alkaline pH, at a temperature preferably ranging from 30° C. to 100° C., preferably of about 40° C. to 60° C.

The oxidation of the compound of formula (XII) is generally carried out in water, preferably at about pH 8-9, this value being maintained by addition of a strong base, such as NaOH.

Preferably, the oxidant used in respect of the dimethylbenzene derivative of formula (XII) amounts to from 2 to 5 mols, e.g. 3 mols; the halide is preferably in a stoichiometric amount in respect of the derivative of formula (XII); the catalyst is typically in an amount ranging from 1% to 30% in mols, preferably from 10% to 25% in mols in respect of the derivative of formula (XII).

Several derivatives of formula (XII) are commercially available or may be prepared by conventional methods.

Preferred derivatives of formula (VII) above are the ones in which R₂ is a saturated, straight or branched C₁ -C₄ alkyl group, especially CH₃.

Out of the derivatives of formula (VIII), particularly preferred are the ones in which R₂ and R₃, which may be the same or different one from the other, are C₁ -C₄ alkyl groups, preferably saturated, more particularly the ones in which R₂ =R₃ =CH₃.

In step 1), the temperature preferably ranges from about 30° C. to 100° C., typically from about 50° C. to 70° C.

Furthermore, R₃ OH is preferably CH₃ OH and is preferably used as a reaction solvent, in an amount, e.g., ranging from 0.5 to 2 ml, preferably of 1 ml per mmol of the derivative of formula (VII).

Preferably, the Cu(I) salt is a halide, such as CuCl, and the acid is an inorganic strong acid, typically a hydrogen halide, such as HCl; furthermore, the Cu(I) salt and the acid are preferably used in a stoichiometric amount in respect of the compound of formula (VII), as well as up to 2 mols per mol of (VII).

Preferred derivatives of formula (IX) are the ones in which R₂ and R₃, which may be the same or different one from the other, are C₁ -C₄ alkyl groups, preferably saturated, and especially the ones in which R₂ =R₃ =CH₃ ; furthermore, Hal is preferably Cl or Br and more preferably Cl.

The temperature of step 2) preferably ranges from about 50° C. to 120° C., more preferably from about 60° C. to 90° C.; the halogenating agent is, e.g., thionyl chloride, PCl₅ or PCl₃.

Typically, thionyl chloride is used, e.g., as a reaction medium, in a quantity typically ranging from about 1 to 2 ml per 100 mmols of the derivative of formula (VIII). The reaction is preferably carried out at the reflux temperature of the reaction mixture (about 78° C. to 80° C.).

Step 2) may be also carried out in the presence of a diluent or of an inert organic solvent.

Preferred derivatives of formula (X) are the ones in which R₁ is --OR', and R' and R4, which may be the same or different one from the other, are preferably a saturated, straight or branched C₁ -C₄ alkyl, and more preferably the ones in which R₁ is --OCH₃ and R₄ is CH₃.

The temperature of step 3) preferably ranges from about 40° C. to 100° C., more preferably from about 40° C. to 60° C.

Furthermore, the catalyst is selected out of the catalysts commonly used in Friedel-Crafts reactions (alkylations or acylations) and is typically an aluminium halide, such as AlCl Step 3) preferably utilizes stoichiometric ratios of the derivative of formula (X) to the derivative of formula (IX) and amounts of Friedel-Crafts catalyst typically ranging from 0.1% to 10% in mols, more typically from about 1% to 2% in mols in respect of the derivative of formula (IX).

According to a preferred embodiment of the present invention, step 3) is carried out in the absence of solvents, simply by mixing the substrates of formulas (IX) and (X) with the catalyst and raising the reaction temperature to the selected value. Alternatively, however, step 3) may be also carried out in the presence of diluents or of inert organic solvents.

Preferred derivatives of formula (XI) are the ones in which R₁ is --OR', and R, R₂, R₃ and R₄, which may be the same or different one from another, are preferably a saturated, straight or branched C₁ -C₄ alkyl, more preferably the ones in which R₁ is --OCH₃ and R₂ =R₃ =CH₃.

In the hydrolysis (step 4), the temperature preferably ranges from 30° C. to 100° C. and more preferably is of about 80° C. Furthermore, the base is preferably an alkaline hydroxide, such as NaOH, said base being used in a quantity preferably ranging from about 0.5 to 1 mol per mol of compound of formula (XI).

Step 4) is preferably carried out in a water-alcohol mixture, alcohol being, e.g., methanol, ethanol, e.g. in 50:50 water/ethanol.

At the end of the reaction, diphenylketone (II)A is recovered from the reaction medium by acidification, typically with HCl.

Preferred derivatives of formula (II)A are the ones in which R₂ is a C₁ -C₄ alkyl group, preferably saturated, and more typically R₂ =CH₃.

The derivatives of formula (X), in which R₁ is --NR'R", --SR' or --OH can be obtained from the corresponding derivatives, in which R₁ is --OR' as above defined, by conventional methods.

The derivatives of formula (X), in which R₁ is --OR' as above defined, are e.g. prepared by esterification of 3-aminobenzoic acid, followed by acylation of the aminic function.

For example, 3-aminobenzoic acid is treated with an R'OH alcohol, where R' is as defined above and is preferably a C₁ -C₄ alkyl group (more preferably CH₃), in the presence of an acid catalyst, preferably at a temperature ranging from 30° C. to 100° C., e.g. from 50° C. to 70° C. to give the corresponding ester of formula (XIII) ##STR15## in which R' is as defined above and more preferably is CH₃.

R' OH is preferably CH₃ OH and is typically used as a reaction solvent; furthermore, the acid catalyst is, e.g. concentrated H₂ SO₄, in a quantity ranging from 1 to 5 ml, e.g. 3 ml, per 100 mmols of substrate.

The resulting derivative of formula (XIII) is treated with an acylating agent, preferably with the R₄ COOH acid anhydride. where R₄ is as defined above and is preferably a saturated C₁ -C₄ alkyl group, preferably in the presence of an acid catalyst. such as the R₄ COOH acid, at a temperature preferably ranging from about 80° C. to about 120° C. more preferably at about 100° C. to 120° C.

Preferably, R₄ is CH₃, the anhydride is acetic anhydride and the acid is acetic acid, used, e.g. as reaction solvents, the acid. e.g., in an amount of about 2 to 10 ml. preferably 5 ml. per 100 mmols of substrate of formula (X), and the anhydride in an amount of about 1 to 2 ml, e.g., about 1.2 to 1.4 ml, per 100 mmols of substrate of formula (XIII).

The compounds of formula (X) may be anyhow prepared by other conventional methods.

The following examples are conveyed by way of indication, not of limitation, of the present invention.

EXAMPLE 1 Preparation of the Intermediate of Formula (III) in which R₁ is --OH and R₂ is --CH₃

The intermediate of formula (II) (0.01 mol), in which R₅ is H, R₁ is --OH and R₂ is --CH₃, was suspended in 30 ml concentrated strong acid, such as H₂ SO₄ or CF₃ SO₃ H, more preferably CF₃ SO₃ H. The resulting mixture was heated to 150° C. for 2 hrs. under constant stirring. After said 2 hr-period, the solution was cooled to room temperature and neutralized with 10% aqueous NaOH.

The precipitate was filtered, washed with water and evaporated to dryness, to give a crystalline product corresponding to the intermediate of formula (III) (0.0089 mol), in which R₁ is --OH and R₂ is --CH₃. Total yield 88%. Melting point 226° C.

The product was analysed by TLC on silica gel and identified by IR spectrometry.

The analytical values were in agrement with the theoretical values.

EXAMPLE 2 Preparation of the Intermediate of Formula (IV) in which R₂ is --CH₃

The intermediate of formula (III) (0.01 mol), in which R₁ is OH and R₂ is --CH₃, obtained as per Example 1. was dissolved in a 1:3 sulphuric acid/water mixture (v/v), in a quantity of about 20 to 35 ml.

The resulting mixture was cooled to 0° C. to 5° C., allowed to stir until complete dissolution of the intermediate of formula (III), and added with NaNO₂ (0.015 mol) dissolved in 10 ml cool water (50° C.).

The reaction mixture was left under stirring for an additional 15 min. and added with 100 ml of a 1:1 water-sulphuric acid mixture (v/v). The solution was heated to 150° C. for 1 hr. under constant stirring. After cooling to room temperature, the resulting precipitate was collected by filtration in vacuo, washed with water and dried under reduced pressure at 50° C. A yellow-brown crystalline solid was obtained (m.p. 261° C.). corresponding to the intermediate of formula (IV) (0.0085 mol) in which R₂ is --CH₃.

EXAMPLE 3 Preparation of Rhein [compound of formula (V)]

The product obtained as per Example 2 [intermediate of formula (IV) in which R₂ is --CH₃ ] was suspended in 100 ml glacial acetic acid containing a 48% HBr solution in water (10 ml). The reaction mixture was heated to reflux for 3 hrs., cooled to room temperature and filtered.

The precipitate obtained was collected by filtration in vacuo, washed with water and dried under reduced pressure.

Recrystallization from methanol gave a yellow-greenish needle-shaped product (m.p. 244° C. to 246° C.). Yield 79% to 83%.

Elemental analysis, IR and Rf values are in accordance with the values found for rhein [compound of formula (V)].

EXAMPLE 4 Preparation of Diacerhein

Rhein (0.01 mol) obtained as per Example 3 was suspended in 100 ml glacial acetic acid. The resulting suspension was added with acetic anhydride (0.03 mol) and one drop of concentrated sulphuric acid. and heated to 80° C. under stirring for 1 hr. The solution was allowed to cool to room temperature. A yellow-greenish precipitate was collected by filtration in vacuo, washed with water and dried under reduced pressure. Total yield 98%. Melting point 247° C.

IR spectrum: v_(max) 1733 cm⁻¹ (ester), 1701 cm⁻¹ (carboxyl), 1689 cm⁻¹ (carbonyl).

Elemental analysis: Calcd for C₁₉ H₁₂ O₈ : C, 61,96; H. 3.29; Found: C, 62.07; H 3.39.

The above data prove that the product obtained is identical with an authentic diacerhein sample. DIPHENYLONE OF FORMULA (II)A IN WHICH R₂ IS --CH₃

EXAMPLE 5 Preparation of Methoxyphthalic Acid [derivative of formula (VII) in which R₂ is CH₃ ]

A mixture was made up as follows: 0.1 mol of 2,3-dimethylmethoxybenzene [derivative of formula (XII) in which R₂ is CH₃ ], added with 0.3 mol of NaClO, as an aqueous solution containing 15% active Cl; n-butylbromide (0.1 mol); RuCl₃.3H₂ O (0.02 mol).

The mixture was vigorously stirred at 50° C. and the pH of the solution was maintained at 8-9 through the addition of 2M NaOH.

When the pH of the solution remained constant, the reaction mixture was allowed to stir for an additional 1 hr., cooled to room temperature and acidified with a concentrated HCl-H₂ O mixture until complete precipitation of methoxyphthalic acid. The precipitate was collected by filtration and dried under reduced pressure. The methoxyphthalic acid yield was 98%.

EXAMPLE 6 Preparation of Methoxyphthalic Acid Monomethylester [derivative of formula (VIII) in which R₂ =R₃ =CH₃ ]

A solution of methoxyphthalic acid obtained as per Example 5 (0.1 mol) in 100 ml methanol was added with CuCl (0.1 mol) and HCl (0.1 mol). The solution was heated to reflux for 30 min. The clear solution obtained was evaporated to dryness under reduced pressure. The residue obtained was dissolved in a 1:3 water-methanol mixture and acidified. The product was separated by cooling, collected by filtration and air dried. The product yield was 63-66%.

EXAMPLE 7 Preparation of Methoxyphthalic Acid Monomethylester Chloride [derivative of formula (IX) in which R₂ =R₃ =CH₃ and Hal is Cl]

The methoxyphthalic acid monomethylester obtained as per Example 6 (0.1 mol) was suspended in thionyl chloride (1.5 ml). The resulting suspension was slowly heated to reflux until complete dissolution of the solid material.

After refluxing for an additional 30 min., excess thionyl chloride was removed under reduced pressure and the residue was recrystallized from toluene.

The title product yield was 84%.

EXAMPLE 8

a) Preparation of 3-Aminobenzoic Acid Monomethylester [derivative of formula (XIII) in which R₁ is --OCH₃ ]

3-Aminobenzoic acid (0.1 mol) was added with 50 ml methanol. The mixture was cooled in an ice bath and slowly added with 3 ml concentrated H₂ SO₄. The components were mixed and refluxed for 1 hr.

The solution was cooled, settled in a separatory funnel containing 50 ml water. The vessel was fed with 35 ml t-butylmethylether. After mixing, the aqueous layer was removed and the ethereal phase was washed first with 25 ml water and then with 25 ml 1.5M NaHCO₃. The ethereal phase was evaporated under an aspirating tube.

b) Preparation of 3-Aminobenzoic Acid Monomethylester N-Acetyl Derivative [derivative of formula (X) in which R₁ is --OCH₃ and R₄ is CH₃ ]

The 3-aminobenzoic acid monomethylester obtained as per a) above (0.1 mol) was added with acetic acid (5 ml).

The resulting mixture was heated slightly above 100° C. and the solution was allowed to stir.

The temperature was allowed to decrease to 100° C. and acetic anhydride (1.3 ml) was added. The mixture was left under stirring until the temperature lowered to 75° C. and water (1 ml) was added. Water was removed in vacuo and the resulting oily syrup was resuspended in cyclohexane (5 ml). The temperature was raised to remove the trace water from the syrup as a cyclohexane-water azeotrope. The title product yield was 89% to 93%.

EXAMPLE 9 Preparation of Diphenylketone of Formula (XI) in which R₁ is --OCH₃ and R₂ =R₃ =R₄ =CH₃

Methoxyphthalic acid monomethylester chloride (0.1 mol) and 3-aminobenzoic acid monomethylester N-acetyl derivative were caused to react in a 10×100 mm tube.

The reaction mixture was cooled in an ice bath and added with anhydrous AlCl₃ (200 mg). The tube was sealed with a septum connected with a Teflon tube immersed in a moist cotton plug trapping the HCl being developed during the reaction. The tube content was carefully mixed and cautiously heated in a hot water vessel. Gaseous HCl evolution was controlled by repeatedly heating and cooling the reaction mixture. The reaction was continued for about 15 min. at 50° C. until gas evolution ceased completely.

The mixture was cooled in an ice bath and added with ice in small pieces (1 g). Each piece of ice was allowed to react before adding the successive piece. The tube content was carefully mixed, cooled to room temperature, added with 0.5 ml water and 5 ml t-butylether, and mixed. The aqueous phase was removed. Once extraction had been repeated, concentrated HCl (0.2 ml) in 0.5 ml water was added. The organic layer was transferred into a small test tube and evaporated to dryness.

Diphenylketone yield was 79%.

EXAMPLE 10 Hydrolysis of Diphenylketone of Formula (XI), in which R₁ is --OCH₃, R₂ =R₃ =R₄ =CH₃, to give the dimethylketone of formula (II)A, in which R₂ is CH₃

The diphenylketone obtained as per Example 9 (0.1 ml) was treated with a 50:50 water-ethanol mixture (3 ml) containing NaOH (about 1.89 to 3.6 g). The mixture was cautiously heated to reflux in a sand bath for 30 min. Once the reaction had been completed, the solution was acidified, the precipitate was collected by filtration, and air dried. The product yield was 90%. 

I claim:
 1. Process for producing rhein and rhein derivatives of formula (I) ##STR16## in which R_(A) is H, acyl, alkyl or aromatic group comprising the steps of:a) treating a diphenylketone of formula (II) ##STR17## in which R₁ is --OH, --OR', --NH₂, --NHR', --NR'R", --SH or --SR', where R' and R", which may be the same or different one from another, each represents alkyl or aromatic groups,R₂ is H or a protective group of the --OH function, R₅ is H or C₁ -C₄ alkyl, with a strong concentrated acid to give the 1-aminoanthraquinone derivative of formula (III) ##STR18## in which R₁ and R₂ are as defined above: b) converting the --NH₂ group to --OH, via the following steps: b') treating the derivative of formula (III) obtained in step a) with a diazotising agent, and b") warm treating the resulting product with a strong acid in an aqueous medium to give the compound of formula (IV) ##STR19## in which R₂ is as defined above; c) when R₂ is a protective group, removing R₂ in any process step, on the compound of formula (II), (III) or (IV), in which R₂ is a protective group as defined above, to give the rhein of formula (V) ##STR20## d) when R_(A) is acyl, treating the rhein of formula (V) with an acylating agent, or, when R_(A) is alkyl or aromatic group, with a base and with the corresponding etherifying agent.
 2. A process as claimed in claim 1 for producing the derivative of formula (I) in which R_(A) is --COCH₃ (diacerhein), wherein step d) is an acetylation step.
 3. A process as claimed in claim 1, wherein:the reaction mixture coming from diazotisation (step b') is directly subjected to step b") without prior isolation of the intermediate diazo derivative; step c), i.e. removal of protective group R₂, is carried out as the last step of the synthesis on the compound of formula (IV) coming from step b"), in which R₁ is as defined above and R₂ is a protective group as defined above, after performing, in sequence, steps a), b') and b").
 4. A process as claimed in claim 1, wherein:step a) utilizes the diphenylketone of formula (II), in which R₅ is H, R₁ is --OH, and R₂ is a saturated, straight or branched C₁ -C₄ alkyl group to give the corresponding 1-aminoanthraquinone derivative of formula (III), in which R₁ is --OH and R₂ is a saturated, straight or branched C₁ -C₄ alkyl group; the reaction mixture from step b') is directly subjected to step b"), without prior isolation of the intermediate diazo derivative, to give the corresponding phenol derivative of formula (IV), in which R₂ is a saturated, straight or branched C₁₋₄ alkyl; in step c), the derivative of formula (IV) as obtained above is subjected to acid hydrolysis to give the rhein of formula (V).
 5. A process as claimed in claim 1, wherein, in step a) the concentrated strong acid is concentrated H₂ SO₄, fuming H₂ SO₄ or CF₃ SO₃ H and the temperature ranges from 0° C. to 250° C.
 6. A process as claimed in claim 1, wherein the temperature of step a) ranges from 100° C. to 250° C.
 7. A process as claimed in claim 6, wherein the temperature of step a) ranges at least from 140° C. to 160° C.
 8. A process as claimed in claim 1, wherein diazotisation (step b') is carried out by cold treatment of the product of formula (II) with nitrous acid in an aqueous medium.
 9. A process as claimed in claim 8, wherein the temperature of step b') ranges from 0° C. to 8° C.
 10. A process as claimed in claim 8, wherein, in step b'), the nitrous acid is generated in the reaction medium by the action of a strong acid on an alkali metal nitrite.
 11. A process as claimed in claim 10, wherein the nitrite is NaNO₂ and the strong acid is H₂ SO₄.
 12. A process as claimed in claim 1, wherein the temperature of step b") ranges from 100° C. to 250° C.
 13. A process as claimed in claim 12, wherein the temperature of step b") ranges from 140° C. to 150° C.
 14. A process as claimed in claim 12, wherein the strong acid is H₂ SO₄.
 15. A process as claimed in claim 1, wherein steps b') and b") are carried out in a reaction medium consisting of a strong acid-water mixture in ratios ranging from 1:0.5 to 1:5 (v/v).
 16. A process as claimed in claim 1, wherein step c) is an acid hydrolysis carried out at a temperature ranging from 90° C. to 160° C.
 17. A process as claimed in claim 1, wherein step c) is carried out with concentrated HBr in glacial acetic acid as diluent.
 18. A process as claimed in claim 2, wherein step d) is carried out at a temperature ranging from 50° C. to 100° C.
 19. A process as claimed in claim 18, wherein the temperature ranges from 70° C. to 90° C.
 20. A process as claimed in claim 18, wherein rhein is treated with acetic anhydride, in glacial acetic acid, in the presence of a catalytic quantity of concentrated H₂ SO₄. 